Synthesis and evaluation of the α-glucosidase inhibitory activity of 3-[4-(phenylsulfonamido)benzoyl]-2H-1-benzopyran-2-one derivatives

Article abstract of DOI:10.1016/j.ejmech.2009.12.031

In the course of studies directed toward the discovery of novel non-sugar α-glucosidase inhibitors for the treatment of diabetes, a series of 3-[4-(phenylsulfonamido)benzoyl]-2H-1-benzopyran-2-one derivatives was synthesized and evaluated as α-glucosidase inhibitors. Most compounds showed good inhibitory activity with IC₅₀ values ranging from 0.0645?μM to 26.746?μM. 7-Hydroxy-6-methoxy-3-[4-(4-methylphenylsulfonamido)benzoyl]-2H-1-benzopyran-2-one 7u manifested the most potent inhibitory activity with an IC₅₀ value of 0.0645 μM.

Full text of DOI:10.1016/j.ejmech.2009.12.031

European Journal of Medicinal Chemistry 45 (2010) 1250–1255
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Synthesis and evaluation of the
a-glucosidase inhibitory activity of
3-[4-(phenylsulfonamido)benzoyl]-2H-1-benzopyran-2-one derivatives
,
b
a
a
a
a
Shaojie Wang a , Jufang Yan , Xiaoyan Wang , Zhuo Yang , Fengwei Lin , Tingjian Zhang
*
a Key Laboratory of New Drugs Design and Discovery of Liaoning Province, Shenyang Pharmaceutical University, 103 Culture Road, Shenhe District, Shenyang 110016, China
b Drug Screening Center, Di Ao Pharmaceutical Group, Chengdu 123388, China
a r t i c l e i n f o
a b s t r a c t
Article history:
In the course of studies directed toward the discovery of novel non-sugar a-glucosidase inhibitors for the
Received 10 October 2009
Received in revised form
8 December 2009
Accepted 12 December 2009
Available online 22 December 2009
treatment of diabetes, a series of 3-[4-(phenylsulfonamido)benzoyl]-2H-1-benzopyran-2-one derivatives
was synthesized and evaluated as -glucosidase inhibitors. Most compounds showed good inhibitory
activity with IC50 values ranging from 0.0645 M to 26.746 M. 7-Hydroxy-6-methoxy-3-[4-(4-meth-
ylphenylsulfonamido)benzoyl]-2H-1-benzopyran-2-one 7u manifested the most potent inhibitory
activity with an IC50 value of 0.0645 M.
a
m
m
m
Ó 2009 Elsevier Masson SAS. All rights reserved.
Keywords:
Chalcone
3-[4-(Phenylsulfonamido)benzoyl]-2H-1-
benzopyran-2-one
a
-Glucosidase inhibitor
1. Introduction
be structurally constrained analogues of chalcones, with the chal-
cone substructure incorporated into the benzopyran backbone.
Chalcones demonstrate various biological activities, including
antimalarial, antifungal, anti-inflammatory, and cytotoxic activities
[10–13]. Chalcones with sulfonamide substitution have recently
received significant attention for their biological activities, such as
their fungicidal, antimalarial, antileishmanial, and anti-interleukin-
5 activities [14–17]. Seo et al. found that aminochalcones, such
a-Glucosidase (EC 3.2.1.20) is located in the brush-border
surface membrane of intestinal cells. It is responsible for catalyzing
the final step in the digestive process of carbohydrates [1]. Mean-
while,
a-Glucosidase inhibitors can retard the gastrointestinal
absorption of dietary carbohydrates by inhibiting the digestion of
polysaccharides and disaccharides, thus lessening the postprandial
increase in the blood glucose level [2]. Several sugar
a-glucosidase
as 4, exhibit a-glucosidase inhibitory activity. Encouraged by the
inhibitors, including acarbose, voglibose, and miglitol are clinically
used in the effective treatment of type 2 diabetes mellitus [3].
However, such inhibitors, which are of great structural diversity,
require tedious multi-steps during preparation. Hence, greater
anti-diabetic sulfonylureas, they further synthesized several phe-
nylsulfonamide chalcones, such as 5 and 6, which displayed higher
a
-glucosidase inhibitory activity compared with their correspond-
ing amino analogues [18]. To investigate the binding mode of
sulfonamide chalcone, a homology-modeled -glucosidase protein
attention is focused on non-sugar
a
-glucosidase inhibitors.
a
Flavones display extensive biological activities, including anti-
cancer, antifungal, antiviral, and anti-inflammatory activities [4–7].
Recent studies indicate that Baicalein 1 and its analogues can
effectively inhibit sucrase [8]. In the course of identifying potential
structure was developed by Bharatham et al. The study found that
the sulfonamide group interacts with Asp349, His348, and Arg212
through hydrogen bonds, and the benzene ring of phenyl-
sulfonamide chalcone is inserted into the pocket comprised of
Tyr71, Phe157, Phe158, and Phe177 through a hydrophobic inter-
action [19]. Thus, the phenylsulfonamide chalcone scaffold may be
a-glucosidase inhibitors from the Indian herb Oroxylum indicum, it
was observed that extracts of this plant possess inhibitory activity,
with Oroxylin A 2, Baicalein 1, and Chrysin 3 posing as the major
isolates for the activity [9]. Actually, flavones can be considered to
useful for designing new a-glucosidase inhibitors.
In this paper, a series of 3-[4-(phenylsulfonamido)benzoyl]-2H-
1-benzopyran-2-one derivatives (Fig. 1), being structurally
constrained analogues of phenylsulfonamide chalcones with the
phenylsulfonamide chalcone substructure incorporated into the
benzopyran backbone, was designed and synthesized to find novel
* Corresponding author. Tel./fax: þ86 24 2398 6421.
E-mail address: sjwang_99@yahoo.com.cn (S. Wang).
non-sugar
a-glucosidase inhibitors and to verify the viability of
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.12.031

S. Wang et al. / European Journal of Medicinal Chemistry 45 (2010) 1250–1255
1251
Fig. 1. Schematic diagram depicting the procedure for the design of the target compounds.
using
one as a scaffold for the design of
glucosidase inhibitory activity of the synthesized compounds was
evaluated on yeast -glucosidase, and their structure–activity
3-[4-(phenylsulfonamido)benzoyl]-2H-1-benzo-pyran-2-
In the R4 ¼ H series, the activity of compound 7b
a
-glucosidase inhibitors. The
a
-
(IC50 ¼ 7.180
(IC50 ¼ 3.283
mM) was lower than that of compound 7a
mM), and compounds 7c and 7d had no activity, sug-
a
gesting that the halogen group at the C6 position could reduce the
relationships were considered.
2. Results and discussion
2.1. Chemistry
activity. As compared to compound 7a, compound 7f
(IC50 ¼ 7.129
possessed lower activity; this bulky group might be unfavorable for
binding with -glucosidase. When C7 was substituted with the
mM) with tert-butyl groups at C6 and C8, respectively,
a
methoxy group, such as compounds 7g and 7k, their activities
disappeared, demonstrating that the methoxy group at the C7
position was deficient for inhibitory activity. When C7 was
substituted with hydroxy, the activity of compound 7h decreased
The synthesis of the target compounds (7a–v) is outlined in
Scheme 1. The treatment of 4-nitrobenzoic acid with thionyl chlo-
ride under reflux resulted in 4-nitrobenzoyl chloride [20]. This then
reacted with ethyl acetoacetate in the presence of sodium ethylate,
and the resulting followed by hydrolysis to afford compound 10,
which was hydrogenated over the Pd/C catalyst to provide
compound 11. Following this, compound 11 was acylated with
benzenesulfonyl chloride and 4-methylbenzenesulfonyl chloride,
respectively, and the two key intermediates 12a and 12b were
obtained [21]. Lastly, the two intermediates were reacted sepa-
rately with substituted salicylaldehydes via Knoevenagel conden-
sation, and 22 target compounds were obtained [22], the structures
of which were fully supported by 1H NMR, IR, and TOF-HRMS
spectral data.
slightly with an IC50 value of 5.766
with diethylamino, the activity of compound 7i (IC50 ¼ 0.294
was enhanced 11-fold compared to that of compound 7a.
Compound 7j (IC50 ¼ 0.199 M) possessed the strongest inhibitory
mM. In the case of C7 substituted
mM)
m
activity of the series, and its activity was 16 times higher than that
of compound 7a, and 29 times higher than that of compound 7h.
Apparently, the methoxy group at the C6 position plays an impor-
tant role in promoting the activity. By comparing two compound
couples, 7h versus 7g and 7j versus 7k, it was obvious that the
methylation of the hydroxy group at the C7 position had a negative
impact on inhibitory activity.
In the R4 ¼ CH3 series, by separately comparing compound 7l
(IC50 ¼ 3.577
(IC50 ¼ 26.746
modification of benzopyranone moiety with halogen groups
m
m
M) with compounds 7m (IC50 ¼ 4.600
mM), 7n
M), and 7o (IC50 > 30 mM), it was observed that the
2.2.
a-Glucosidase inhibitory activity
reduced inhibitory activity. Such
a tendency might act as
The in vitro inhibitory activity of the target compounds was
evaluated spectrophotometrically at 490 nm on yeast -glucosi-
dase, as shown in Table 1. It was proven that most of the 3-[4-
(phenylsulfonamido)benzoyl]-2H-1-benzopyran-2-one derivatives
demonstrated good inhibitory activity with IC50 values ranging
F < Cl < Br; a similar trend could also be found in the R4 ¼ H series.
a
Compound 7q (IC50 ¼ 10.099
mM) with tert-butyl groups at the C6
and C8 positions, possessed lower activity compared to compound
7l, and this was in agreement with compound 7f versus
compound 7a in the R4 ¼ H series. Concerning compounds 7s
from 0.0645 mM to 26.746 mM.
Scheme 1. Synthesis of 3-[4-(phenylsulfonamido)benzoyl]-2H-1-benzopyran-2-one derivatives 7. Reagents and conditions: (a) SOCl2 reflux; (b) ethyl acetoacetate, EtONa in EtOH,
THF, ꢀ10 ꢁC, then rt; (c) H2, Pd/C, EtOH, rt; (d) benzenesulfonyl/4-methylbenzenesulfonyl chloride, pyridine, CH2Cl2,–10 ꢁC, then rt; (e) substituted salicylaldehyde, piperidine, acetic
acid, EtOH, reflux.

1252
S. Wang et al. / European Journal of Medicinal Chemistry 45 (2010) 1250–1255
Table 1
The in vitro inhibitory activity of 3-[4-(phenylsulfonamido)benzoyl]-2H-1-benzopyran-2-one derivatives against yeast
a
-glucosidase.
R3
No
R1
R2
R3
R4
IC50
(m
M)
No
R1
R2
R4
IC50 (mM)
a
a
7a
7b
7c
7d
7e
7f
7g
7h
7i
H
F
Cl
Br
Br
C(CH3)3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
3.283
7.180
7l
H
F
Cl
Br
Br
C(CH3)3
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
3.577
4.600
7m
7n
7o
7p
7q
7r
7s
7t
7u
7v
>30b
26.746
>30b
>30b
7.129
>30b
5.766
>30b
Br
C(CH3)3
Br
C(CH3)3
7.727
10.099
OCH3
OH
N(C2H5)2
OH
H
H
H
H
H
OCH3
OH
N(C2H5)2
OH
H
H
H
H
H
>30b
1.125
0.347
0.0645
5.589
0.294
0.199
7j
7k
OCH3
OCH3
OCH3
OCH3
OCH3
>30b
OCH3
a
IC50 values: the concentration of the inhibitor required to produce 50% inhibition of a-glucosidase.
IC50 > 30 mM was considered to be no inhibitory activity.
b
(IC50 ¼ 1.125
m
M), 7t (IC50 ¼ 0.347
m
M), and 7u (IC50 ¼ 0.0645
m
M),
4.1.1. 4-Nitrobenzoyl chloride 9
the activity increased remarkably in the presence of the hydroxy
or diethylamino groups at the C7 position. By comparing
A mixture of 4-nitrobenzoic acid 8 (150.0 g, 0.9 mol) and thionyl
chloride (210 ml) was stirred under reflux for 5 h. The mixture was
then condensed under reduced pressure, and a yellow solid
(166.8 g) was obtained with a yield of 99.8%. The product was
sufficiently pure to proceed to the next step.
compounds 7s and 7u in relation to compounds 7r (IC50 > 30
and 7v (IC50 ¼ 5.589 M), respectively, it was noted that the
mM)
m
methylation of the hydroxy group at the C7 position was not
beneficial for their activities; moreover, compound 7u with
a methoxy group at the C6 position showed the strongest inhibi-
tory activity between the two series. In general, most compounds
in the R4 ¼ CH3 series showed higher activities than those in the
R4 ¼ H series. The activities of compounds 7m, 7n, 7p, 7s, 7u, and
7v were higher than those of compounds 7b, 7c, 7e, 7h, 7j, and 7k,
respectively.
4.1.2. Ethyl 3-(4-nitrophenyl)-3-oxopropanoate 10
A solution of sodium ethylate prepared from sodium metal
(13.8 g, 0.6 mol) and anhydrous ethanol (230 ml) was added
dropwise to ethyl acetoacetate (117 g, 0.9 mol) at ꢀ10 ꢁC. The
solution was stirred at room temperature for 1–2 h, and a solu-
tion of 4-nitrobenzoyl chloride (167 g, 0.9 mol) in dry THF
(1200 ml) was added dropwise at ꢀ10 ꢁC. The solution was stir-
red at room temperature for 4–5 h. The THF was evaporated
under reduced pressure. The residue was mixed with ether
(1000 ml) and was then filtered. The cake was washed with ether
and mixed with water (1000 ml). The mixture was warmed to
35 ꢁC, and a solution of ammonium chloride (60 g) and 25%
ammonium hydroxide (60 ml) was added. After stirring over-
night, the solution was cooled to 5 ꢁC and was left to stand for
2 h. After the filtering and drying process, 110 g of solid was
obtained and it was purified by column chromatography (chlo-
roform) to give 10 as a yellow solid (88 g, 41.2%), mp 70–72 ꢁC
(68–71 ꢁC [23]).
Finally, by comparing compounds 7s and 7u in relation to
compounds 19 (IC50 ¼ 0.98
mM) and 20 (IC50 ¼ 0.40
mM) in refer-
ence 18 [18], respectively, it was interesting to find that compound
7s was comparable to compound 19, whereas compound 7u
showed inhibitory activity that was 6-fold stronger than that of
compound 20.
3. Conclusion
In summary, the results showed that 3-[4-(phenyl-
sulfonamido)benzoyl]-2H-1-benzopyran-2-one derivatives repre-
sent a new class of strong non-sugar
3-[4-(phenylsulfonamido)benzoyl]-2H-1-benzopyran-2-one might
be a suitable scaffold to use in the design of new -glucosidase
a-glucosidase inhibitors and
a
4.1.3. Ethyl 3-(4-aminophenyl)-3-oxopropanoate 11
inhibitors. Among the compounds synthesized, compound 7u
showed the strongest inhibitory activity. Further investigations into
the structure–activity relationships together with tests on
mammalian animal models are currently in progress in our
laboratory.
A solution of ethyl 3-(4-nitrophenyl)-3-oxopropanoate 10 (88 g,
0.37 mol) in anhydrous ethanol (1000 ml) was hydrogenated over
10% Pd/C (1 g) at room temperature for 5 h. The solvent was filtered
and evaporated under reduced pressure to produce a light yellow
solid (57.3 g, 74.6%), mp 82–84 ꢁC (84.3–84.5 ꢁC [24]).
4.1.4. Ethyl 3-oxo-3-[4-(phenylsufonamido)phenyl]propanoate 12a
A mixture of ethyl 3-(4-aminophenyl)-3-oxopropanoate 11
(15 g, 0.04 mol), dry pyridine (8.6 g, 0.11 mol), and dry methylene
chloride (90 ml) was stirred and cooled to ꢀ10 ꢁC. Phenylsulfonyl
chloride (14.5 g, 0.08 mol) in dry methylene chloride (45 ml) was
added dropwise at –5–0 ꢁC. The mixture was then stirred at room
temperature for 5 h. The solution was washed with a 5% HCl solu-
tion (23 ml ꢂ 3), and water (20 ml ꢂ 3). The organic phase was then
collected and dried overnight over anhydrous Na2SO4. After
filtering, the solvent was evaporated under reduced pressure and
the residue was recrystallized from anhydrous ethanol. A white
solid was obtained (22.3 g, 83%), mp 112–113 ꢁC; 1H NMR (DMSO-
4. Experimental protocols
4.1. Chemistry
Melting points were recorded using YRT-3 melting point appa-
ratus and were uncorrected. The 1H NMR spectra were recorded in
DMSO-d6 on a Bruker ARX-300 spectrometer, and chemical shifts
(d) were expressed in ppm, downfield from the TMS and were used
as the internal standard. Coupling constant (J) values were in Hz.
The IR spectra were determined as KBr pellets on the Bruker IFS-55
spectrometer and were expressed in cmꢀ1. The progress of the
reactions was monitored by TLC using several solvent systems with
different polarities. The TOF-HRMS spectra were determined using
an Agilent 1100 instrument. All solvents and reagents were of
analytical grade.
d6, ppm):
d
1.14 (t, 3H, J ¼ 6.9 Hz, CH3), 4.07 (m, 4H, 2CH2), 7.22 (d,
2H, J ¼ 8.7 Hz, arom), 7.61 (m, 3H, arom), 7.84 (m, 4H, arom), 10.97
(s, 1H, NH).

S. Wang et al. / European Journal of Medicinal Chemistry 45 (2010) 1250–1255
1253
4.1.5. Ethyl 3-[4-(4-methylphenylsulfonamido)phenyl]-3-
238 ꢁC; 1H NMR (DMSO-d6, ppm):
d
1.31 (s, 9H, 3CH3), 1.46 (s, 9H,
oxopropanoate 12b
3CH3), 7.23 (d, 2H, J ¼ 8.4 Hz, arom), 7.58–7.68 (m, 5H, arom), 7.81–
7.87 (m, 4H, arom), 8.28 (s, 1H, H-4), 11.02 (s, 1H, NH); IR (KBr,
cmꢀ1): 3221, 2966, 1748, 1648, 1579, 1577, 1513, 1238, 1193, 1160,
851, 792; TOF-HRMS: m/z 540.1818 [M þ Na]þ (C30H31NNaO5S
requires 540.1821).
The synthetic procedure was similar to that for 12a.
A
white solid weighing 13.6 g was obtained, with a yield of 52%, mp
140–141 ꢁC; 1H NMR (DMSO-d6, ppm):
d
1.11 (t, 3H, J ¼ 6.9 Hz,
CH2CH3), 2.33 (s, 3H, CH3), 4.07 (m, 4H, 2CH2), 7.21 (d, 2H, J ¼ 8.7 Hz,
arom), 7.37 (d, 2H, J ¼ 8.1 Hz, arom), 7.73 (d, 2H, J ¼ 8.1 Hz, arom),
7.82 (d, 2H, J ¼ 8.7 Hz, arom), 10.89 (s, 1H, NH).
4.1.6.7. 7-Methoxy-3-[4-(phenylsulfonamido)benzoyl]-2H-1-benzo-
pyran-2-one 7g. Yield 93.3%, an orange solid, mp 207–208 ꢁC; 1H
4.1.6. General procedure for the synthesis of compounds 7a–v
NMR (DMSO-d6, ppm):
d
3.90 (s, 3H, OCH3), 7.02 (d, 1H, J ¼ 8.4 Hz,
A
mixture of 12 (1.4 mmol), substituted salicylaldehyde
H-6), 7.08 (s, 1H, H-8), 7.21 (d, 2H, J ¼ 8.7 Hz, arom), 7.57–7.66 (m,
3H, arom), 7.74–7.80 (m, 3H, arom), 7.86 (d, 2H, J ¼ 6.9 Hz, arom),
8.29 (s, 1H, H-4), 10.99 (s, 1H, NH); IR (KBr, cmꢀ1): 3146, 1694, 1661,
1603, 1558, 1505, 1227, 1161, 840, 786; TOF-HRMS: m/z 458.0668
[M þ Na]þ (C23H17NNaO6S requires 458.0674).
(1.6 mmol), five drops of piperidine, one drop of glacial acetic acid,
and ethanol (10 ml) was stirred under reflux in an argon atmo-
sphere for 0.5 h. The mixture was cooled to room temperature and
was filtered to collect the solid (if there was no precipitate, water
(25 ml) was added), then it was washed with a small amount of
ethanol. In most cases, the products were sufficiently pure. Prod-
ucts with impurities could be purified by column chromatography
(petroleum ether–ethyl acetate 100:0–300).
4.1.6.8. 7-Hydroxy-3-[4-(phenylsulfonamido)benzoyl]-2H-1-benzo-
pyran-2-one 7h. Yield 23.5%, a yellow solid, mp 140–141 ꢁC; 1H
NMR (DMSO-d6, ppm):
d
6.70 (d, 1H, J ¼ 2.1 Hz, H-8), 6.84 (dd, 1H,
J ¼ 8.4 and 2.1 Hz, H-6), 7.20 (d, 2H, J ¼ 8.7 Hz, arom), 7.59–7.68 (m,
4H, arom), 7.76 (d, 2H, J ¼ 8.7 Hz, arom), 7.86 (d, 2H, J ¼ 7.2 Hz,
arom), 8.24 (s, 1H, H-4), 10.93 (s, 1H, OH), 10.96 (s, 1H, NH); IR (KBr,
cmꢀ1): 3218, 1714, 1600, 1507, 1227, 1159, 852, 790; TOF-HRMS: m/z
444.0510 [M þ Na]þ (C22H15NNaO6S requires 444.0518).
4.1.6.1. 3-[4-(phenylsulfonamido)benzoyl]-2H-1-benzopyran-2-one
7a. Yield 51.4%, a white solid, mp 159–161 ꢁC; 1H NMR (DMSO-d6,
ppm):
d
7.22 (d, 2H, J ¼ 8.7 Hz, arom), 7.42–7.44 (m,1H, H-8), 7.47–7.49
(m, 1H, H-6), 7.57–7.66 (m, 3H, arom), 7.70–7.72 (m, 1H, H-7), 7.81–
7.88 (m, 5H, arom), 8.33 (s, 1H, H-4), 11.04 (br s, 1H, NH); IR (KBr,
cmꢀ1): 3173, 1710, 1661, 1607, 1566, 1509, 1266, 1166, 851, 804; TOF-
HRMS: m/z 428.0567 [M þ Na]þ (C22H15NNaO5S requires
428.0569).
4.1.6.9. 7-Diethylamino-3-[4-(phenylsulfonamido)benzoyl]-2H-1-
benzopyran-2-one 7i. Yield 70.3%, a yellow solid, mp 110–111 ꢁC;
The 1H NMR (DMSO-d6, ppm):
d 1.15 (t, 6H, 2CH2CH3), 3.48 (m, 4H,
2CH2CH3), 6.58 (s, 1H, H-8), 6.76 (d, 1H, J ¼ 8.5 Hz, H-6), 7.00 (d, 2H,
J ¼ 8.5 Hz, arom), 7.51–7.57 (m, 6H, arom), 7.80 (d, 2H, J ¼ 5.7 Hz,
arom), 8.07 (s, 1H, H-4); IR (KBr, cmꢀ1): 3444, 3057, 2972, 1709,
1579, 1506, 1236, 1181, 1133, 830, 791; TOF-HRMS: m/z 477.1481
[M þ H]þ (C26H24N2NaO5S requires 477.1484).
4.1.6.2. 6-Fluoro-3-[4-(phenylsulfonamido)benzoyl]-2H-1-benzo-
pyran-2-one 7b. Yield 50.5%, a light yellow solid, mp 185–186 ꢁC;
1H NMR (DMSO-d6, ppm):
d
7.22 (d, 2H, J ¼ 8.7 Hz, arom), 7.56–7.70
(m, 6H, arom), 7.83–7.88 (m, 4H, arom), 8.28 (s, 1H, H-4), 11.05 (s,
1H, NH); IR (KBr, cmꢀ1): 3197, 1705, 1673, 1602, 1572, 1507, 1282,
1247, 1163, 844, 791; TOF-HRMS: m/z 446.0456 [M þ Na]þ
(C22H14FNNaO5S requires 446.0474).
4.1.6.10. 7-Hydroxy-6-methoxy-3-[4-(phenylsulfonamido)benzoyl]-
2H-1-benzopyran-2-one 7j. Yield 20.0%, a brown solid, mp 142–
144 ꢁC; 1H NMR (DMSO-d6, ppm):
d 3.81 (s, 3H, OCH3), 6.84 (s, 1H,
4.1.6.3. 6-Chloro-3-[4-(phenylsulfonamido)benzoyl]-2H-1-benzo-
H-8), 7.21 (d, 2H, J ¼ 8.6 Hz, arom), 7.35 (s, 1H, H-5), 7.59–7.66 (m,
3H, arom), 7.74 (d, 2H, J ¼ 8.6 Hz, arom), 7.86 (d, 2H, J ¼ 7.0 Hz,
arom), 8.21(s, 1H, H-4), 10.74 (s, 1H, OH), 10.96(s, 1H, NH); IR (KBr,
cmꢀ1): 3421, 3215, 2926, 1718, 1560, 1510, 1262, 1159, 852, 807;
TOF-HRMS: m/z 474.0612 [M þ Na]þ (C23H17NNaO7S requires
474.0623).
pyran-2-one 7c. Yield 76.8%, a light yellow solid, mp 225–226 ꢁC;
1H NMR (DMSO-d6, ppm):
d
7.23 (d, 2H, J ¼ 8.4 Hz, arom), 7.52 (d,
1H, J ¼ 8.9 Hz, H-8), 7.60–7.66 (m, 3H, arom), 7.75 (dd, 1H, J ¼ 8.9
and 2.4 Hz, H-7), 7.86 (m, 4H, arom), 7.93 (d, 1H, J ¼ 2.4 Hz, H-5),
8.27 (s, 1H, H-4), 11.06 (br s, 1H, NH); IR (KBr, cmꢀ1): 3200, 1705,
1673, 1600, 1280, 1238, 1163, 844, 787; TOF-HRMS: m/z 462.0175
[M þ Na]þ (C22H14ClNNaO5S requires 462.0179).
4.1.6.11. 6,
benzopyran-2-one 7k. Yield 92.5%, a yellow solid, mp 248–249 ꢁC;
1H NMR (DMSO-d6, ppm):
3.80 (s, 3H, OCH3), 3.91 (s, 3H, OCH3),
7-Dimethoxy-3-[4-(phenylsulfonamido)benzoyl]-2H-1-
4.1.6.4. 6-Bromo-3-[4-(phenylsulfonamido)benzoyl]-2H-1-benzo-
d
pyran-2-one 7d. Yield 76.3%, a yellow solid, mp 223–224 ꢁC; 1H
7.16 (s,1H, H-8), 7.22 (d, 2H, J ¼ 8.7 Hz, arom), 7.37 (s,1H, H-5), 7.59–
7.66 (m, 3H, arom), 7.77 (d, 2H, J ¼ 8.7 Hz, arom), 7.86 (d, 2H,
J ¼ 6.9 Hz, arom), 8.24 (s, 1H, H-4), 10.99 (s, 1H, NH); IR (KBr, cmꢀ1):
3424, 3251, 1723, 1652, 1604, 1558, 1506, 1268, 1239, 1163, 858, 831;
TOF-HRMS: m/z 448.0780 [M þ Na]þ (C24H19NNaO7S requires
488.0780).
NMR (DMSO-d6, ppm):
d
7.23 (d, 2H, J ¼ 8.7 Hz, arom), 7.46 (d, 1H,
J ¼ 8.6 Hz, H-8), 7.57–7.66 (m, 3H, arom), 7.84–7.89 (m, 5H, arom),
8.06 (d, 1H, J ¼ 2.3 Hz, H-5), 8.26 (s, 1H, H-4), 11.06 (s, 1H, NH); IR
(KBr, cmꢀ1): 3235, 1753, 1649, 1598, 1513, 1214, 1156, 846, 789; TOF-
HRMS: m/z 505.9674 [M þ Na]þ (C22H14BrNNaO5S requires
505.9674).
4.1.6.12. 3-[4-(4-Methylphenylsulfonamido)benzoyl]-2H-1-benzo-
4.1.6.5. 6, 8-Dibromo-3-[4-(phenylsulfonamido)benzoyl]-2H-1-ben-
pyran-2-one 7l. Yield 83.8%, a white solid, mp 109–110 ꢁC; 1H NMR
zopyran-2-one 7e. Yield 59.8%, an orange solid, mp 237–238 ꢁC; 1H
(DMSO-d6, ppm):
d
2.35 (s, 3H, CH3), 7.21 (d, 2H, J ¼ 8.7 Hz, arom),
NMR (DMSO-d6, ppm):
d
7.23 (d, 2H, J ¼ 8.4 Hz, arom), 7.60–7.66 (m,
7.37–7.50 (m, 4H, arom), 7.65–7.72 (m, 3H, arom), 7.81–7.88 (m, 3H,
arom), 8.33 (s, 1H, H-4), 10.96 (s, 1H, NH); IR (KBr, cmꢀ1): 3226,
1731, 1652, 1598, 1509, 1244, 1186, 1159, 856, 810; TOF-HRMS: m/z
442.0731 [M þ Na]þ (C23H17NNaO5S requires 442.0725).
3H, arom), 7.87 (m, 4H, arom), 8.07 (d, 1H, J ¼ 2.1 Hz, H-5), 8.25 (s,
2H, H-4, 7), 11.07 (s, 1H, NH); IR (KBr, cmꢀ1): 3191, 1716, 1666, 1610,
1549, 1508, 1245, 1216, 1166, 850, 796; TOF-HRMS: m/z 585.8733
[M þ Na]þ (C22H13Br2NNaO5S requires 585.8758).
4.1.6.13. 6-Fluoro-3-[4-(4-methylphenylsulfonamido)benzoyl]-2H-1-
4.1.6.6. 6, 8-Di-tert-butyl-3-[4-(phenylsulfonamido)benzoyl]-2H-1-
benzopyran-2-one 7f. Yield 67.8%, a light yellow solid, mp 237–
benzopyran-2-one 7m. Yield 39.7%, a yellow solid, mp 161–162 ꢁC;
1H NMR (DMSO-d6, ppm):
d
2.35 (s, 3H, CH3), 7.21 (d, 2H, J ¼ 8.4 Hz,

1254
S. Wang et al. / European Journal of Medicinal Chemistry 45 (2010) 1250–1255
arom), 7.39 (d, 2H, J ¼ 8.1 Hz, arom), 7.55–7.61 (m, 2H, H-5, 8), 7.69
(dd, 1H, J ¼ 8.4 and 2.7 Hz, H-7), 7.75 (d, 2H, J ¼ 8.1 Hz, arom), 7.84
(d, 2H, J ¼ 8.7 Hz, arom), 8.27 (s, 1H, H-4), 10.98 (s, 1H, NH); IR (KBr,
cmꢀ1): 3218, 1754, 1597, 1513, 1251, 1188, 1154, 826, 790; TOF-
HRMS: m/z 460.0623 [M þ Na]þ (C23H16FNNaO5S requires
460.0631).
178 ꢁC; 1H NMR: (DMSO-d6, ppm):
d
1.14 (t, 6H, J ¼ 6.6 Hz, 2CH2CH3),
2.34 (s, 3H, CH3), 3.46 (m, 4H, 2CH2CH3), 6.58 (s,1H, H-8), 6.76 (d, 1H,
J ¼ 8.8 Hz, H-6), 7.17 (d, 2H, J ¼ 8.2 Hz, arom), 7.38 (d, 2H, J ¼ 7.8 Hz,
arom), 7.57 (d, 1H, J ¼ 8.7 Hz, H-5), 7.71 (m, 4H, arom), 8.17 (s, 1H, H-
4), 10.84 (s, 1H, NH); IR (KBr, cmꢀ1): 3197, 1720, 1618, 1583, 1508,
1234, 1184, 1159, 920, 786; TOF-HRMS: m/z 513.1499 [M þ Na]þ
(C27H26N2NaO5S requires 513.1460).
4.1.6.14. 6-Chloro-3-[4-(4-methylphenylsulfonamido)benzoyl]-2H-1-
benzopyran-2-one 7n. Yield 43.2%, a yellow solid, mp 186–187 ꢁC;
4.1.6.21. 7-Hydroxy-6-methoxy-3-[4-(4-methyl-
1H NMR (DMSO-d6, ppm):
d
2.35 (s, 3H, CH3), 7.22 (d, 2H, J ¼ 8.7 Hz,
phenylsulfonamido)benzoyl]-2H-1-benzopyran-2-one 7u. Yield 22.0%,
arom), 7.38 (d, 2H, J ¼ 8.1 Hz, arom), 7.53 (d, 1H, J ¼ 8.7 Hz, H-8),
7.75 (m, 3H, arom), 7.84 (d, 2H, J ¼ 8.7 Hz, arom), 7.93 (d, 1H,
J ¼ 2.4 Hz, H-5), 8.26 (s, 1H, H-4), 10.98 (s, 1H, NH); IR (KBr, cmꢀ1):
3215, 1756, 1649, 1597, 1512, 1240, 1189, 1156, 825, 789; TOF-HRMS:
m/z 476.0343 [M þ Na]þ (C23H16ClNNaO5S requires 476.0336).
a yellow solid, mp 176–178 ꢁC; 1H NMR (DMSO-d6, ppm):
d 2.34
(s, 3H, CH3), 3.81 (s, 3H, OCH3), 6.84 (s, 1H, H-8), 7.20 (d, 2H,
J ¼ 8.7 Hz, arom), 7.35–7.39 (m, 3H, arom), 7.72–7.75 (m, 4H,
arom), 8.20 (s, 1H, H-4), 10.73 (br s, 1H, OH), 10.87 (br s, 1H, NH);
IR (KBr, cmꢀ1): 3212, 2929, 1710, 1598, 1564, 1508, 1241, 1199, 1157,
852, 816; TOF-HRMS: m/z 488.0736 [M þ Na]þ (C24H19NNaO7S
requires 488.0780).
4.1.6.15. 6-Bromo-3-[4-(4-methylphenylsulfonamido)benzoyl]-2H-1-
benzopyran-2-one 7o. Yield 72.6%, a yellow solid, mp 187–188 ꢁC;
1H NMR (DMSO-d6, ppm):
d
2.35 (s, 3H, CH3), 7.21 (d, 2H, J ¼ 8.7 Hz,
4.1.6.22. 6, 7-Dimethoxy-3-[4-(4-methylphenylsulfonamido)benzoyl]-
arom), 7.38 (d, 2H, J ¼ 7.8 Hz, arom), 7.45 (d, 1H, J ¼ 9.0 Hz, H-8),
7.75 (d, 2H, J ¼ 7.8 Hz, arom), 7.84 (m, 3H, arom), 8.06 (s, 1H, H-5),
8.25 (s, 1H, H-4), 10.98 (br s, 1H, NH); IR (KBr, cmꢀ1): 3444, 3179,
1714, 1696, 1621, 1581, 1508, 1238, 1190, 1149, 854, 805; TOF-HRMS:
m/z 519.9839 [M þ Na]þ (C23H16BrNNaO5S requires 519.9830).
2H-1-benzopyran-2-one 7v. Yield 84.8%, a fluorescein solid, mp 248–
249 ꢁC; 1H NMR (DMSO-d6, ppm):
d 2.35 (s, 3H, CH3), 3.80 (s, 3H,
OCH3), 3.91 (s, 3H, OCH3), 7.16 (s, 1H, H-8), 7.21(d, 2H, J ¼ 8.7 Hz,
arom) 7.38 (d, 3H, J ¼ 9.1 Hz, H-5, arom), 7.75 (m, 4H, arom), 8.24 (s,
1H, H-4), 10.91 (s, 1H, NH); IR (KBr, cmꢀ1): 3434, 3256, 1711, 1658,
1604, 1564, 1510, 1245, 1202, 1160, 871, 815; TOF-HRMS: m/z
502.0934 [M þ Na]þ (C25H21NNaO7S requires 502.0936).
4.1.6.16. 6, 8-Dibromo-3-[4-(4-methylphenylsulfonamido)benzoyl]-
2H-1-benzopyran-2-one 7p. Yield 65.6%, a yellow solid, mp 227–
228 ꢁC; 1H NMR (DMSO-d6, ppm):
d 2.35 (s, 3H, CH3), 7.21 (d, 2H,
4.2. Assay of the in vitro
a-glucosidase inhibitory activity
J ¼ 8.7 Hz, arom), 7.39 (d, 2H, J ¼ 8.1 Hz, arom), 7.75 (d, 2H,
J ¼ 8.1 Hz, arom), 7.86 (d, 2H, J ¼ 8.4 Hz, arom), 8.07 (d, 1H,
J ¼ 2.1 Hz, H-5), 8.25 (s, 2H, H-4, 7), 10.99 (br s, 1H, NH); IR (KBr,
cmꢀ1): 3244,1747, 1655, 1600, 1510, 1240, 1184, 1160, 859, 796; TOF-
HRMS: m/z 599.8918 [M þ Na]þ (C23H15 Br2NNaO5S requires
599.8915).
A 100 l reaction system containing 0.02 U of
m
a
-glucosidase
(Sigma, G-0660), a test compound, and 67 mM potassium phos-
phate buffer (pH 6.8) was pre-incubated at 37 ꢁC for 10 min. The
reaction was initiated by the addition of 0.1 M maltose, and the
reaction mixture was incubated at room temperature for 10 min.
Then, the glucose-detecting agent (Nanjing Jiancheng Corpora-
tion, China) was added, and the absorbance (A) at 490 nm was
recorded on a SPECTRAmax Plus 384 reader (MD, USA). A nega-
tive control in the absence of a test compound, and a blank
control in the absence of either an enzyme or the test compound
were run simultaneously. The test compounds were initially
4.1.6.17. 6, 8-Di-tert-butyl-3-[4-(4-methylphenylsulfonamido)benzoyl]-
2H-1-benzopyran-2-one 7q. Yield 90.0%, a white solid, mp 218–
219 ꢁC; 1H NMR (DMSO-d6, ppm):
d 1.32 (s, 9H, 3CH3), 1.39 (s, 9H,
3CH3), 2.35 (s, 3H, CH3), 7.22 (d, 2H, J ¼ 8.7 Hz, arom), 7.39 (d, 2H,
J ¼ 8.4 Hz, arom), 7.64 (d,1H, J ¼ 2.1 Hz, H-7), 7.70 (d,1H, J ¼ 2.1 Hz, H-
5), 7.75 (d, 2H, J ¼ 8.1 Hz, arom), 7.84 (d, 2H, J ¼ 8.7 Hz, arom), 8.29 (s,
1H, H-4), 10.96 (s, 1H, NH); IR (KBr, cmꢀ1): 3182, 2962, 1722, 1689,
1659,1601,1510,1238,1186,1162, 848, 813; TOF-HRMS: m/z 554.2033
[M þ Na]þ (C31H33NNaO5S requires 554.1977).
assayed for their inhibition of
10 g/ml.
Next, the inhibition rate was calculated by the equation %
a-glucosidase at a concentration of
m
inhibition ¼ (Anegative ꢀ Atest compound)/(Anegative ꢀ Ablank). If an
inhibition of more than 50% was observed, the compound was
classified as active. The active compounds were consequently
tested at eight concentrations under three times dilution, with each
concentration having two replicates. The IC50 values were calcu-
lated using Xlfit software.
4.1.6.18. 7-Methoxy-3-[4-(4-methylphenylsulfonamido)benzoyl]-2H-
1-benzopyran-2-one 7r. Yield 71.6%, a yellow solid, mp 212–213 ꢁC;
1H NMR (DMSO-d6, ppm):
d 2.34 (s, 3H, CH3), 3.90 (s, 3H, OCH3),
7.01 (d, 1H, J ¼ 8.7 Hz, H-6), 7.08 (s, 1H, H-8), 7.20 (d, 2H, J ¼ 8.7 Hz,
arom), 7.38 (d, 2H, J ¼ 8.1 Hz, arom), 7.76 (m, 5H, arom), 8.29 (s, 1H,
H-4), 10.92 (s, 1H, NH); IR (KBr, cmꢀ1): 3272, 1730, 1651, 1603, 1504,
1227, 1185, 1156, 843, 810; TOF-HRMS: m/z 472.0839 [M þ Na]þ
(C24H19NNaO6S requires 472.0831).
Acknowledgement
The authors are grateful to Ms. Wen Li, Ms. Aihua Song, and Dr.
Weiming Cheng (Analytical Department of Shenyang Pharmaceu-
tical University, Shenyang, China) for the 1H NMR, IR, and TOF-
HRMS spectroscopy data.
4.1.6.19. 7-Hydroxy-3-[4-(4-methylphenylsulfonamido)benzoyl]-2H-
1-benzopyran-2-one 7s. Yield 44.0%, a dark yellow solid, mp 150–
151 ꢁC; 1H NMR (DMSO-d6, ppm):
d 2.34 (s, 3H, CH3), 6.77 (s, 1H, H-
8), 6.84 (d, 1H, J ¼ 8.4 Hz, H-6), 7.20 (d, 2H, J ¼ 8.7 Hz, arom), 7.38 (d,
2H, J ¼ 8.4 Hz, arom), 7.66 (d, 1H, J ¼ 8.4 Hz, H-5), 7.74 (m, 4H,
arom), 8.24 (s, 1H, H-4), 10.88 (s, 1H, OH), 10.92 (s, 1H, NH); IR (KBr,
cmꢀ1): 3426, 1702, 1601, 1508, 1226, 1159, 918, 813; TOF-HRMS: m/z
458.0710 [M þ Na]þ (C23H17NNaO6S requires 458.0674).
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